title: Characterization of intracellular inclusions in the urothelium of mice exposed to inorganic arsenic.
abstract: Inorganic arsenic (iAs) is a known human carcinogen at high exposures, increasing the incidences of urinary bladder, skin, and lung cancers. In most mammalian species, ingested iAs is excreted mainly through urine primarily as dimethylarsinic acid (DMA(V)). In wild-type (WT) mice, iAs, DMA(V), and dimethylarsinous acid (DMA(III)) exposures induce formation of intramitochondrial urothelial inclusions. Arsenite (iAs(III)) also induced intranuclear inclusions in arsenic (+3 oxidation state) methyltransferase knockout (As3mt KO) mice. The arsenic-induced formation of inclusions in the mouse urothelium was dose and time dependent. The inclusions do not occur in iAs-treated rats and do not appear to be related to arsenic-induced urothelial cytotoxicity. Similar inclusions in exfoliated urothelial cells from humans exposed to iAs have been incorrectly identified as micronuclei. We have characterized the urothelial inclusions using transmission electron microscopy (TEM), DNA-specific 4',6-diamidino-2-phenylindole (DAPI), and non-DNA-specific Giemsa staining and determined the arsenical content. The mouse inclusions stained with Giemsa but not with the DAPI stain. Analysis of urothelial mitochondrial- and nuclear-enriched fractions isolated from WT (C57BL/6) and As3mt KO mice exposed to arsenate (iAs(V)) for 4 weeks showed higher levels of iAs(V) in the treated groups. iAs(III) was the major arsenical present in the enriched nuclear fraction from iAs(V)-treated As3mt KO mice. In conclusion, the urothelial cell inclusions induced by arsenicals appear to serve as a detoxifying sequestration mechanism similar to other metals, and they do not represent micronuclei.
authors.affiliation: * Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198-3135;
authors.forename: Puttappa R
authors.initials: PR
authors.lastname: Dodmane
authors.forename: Lora L
authors.initials: LL
authors.lastname: Arnold
authors.forename: David E
authors.initials: DE
authors.lastname: Muirhead
authors.forename: Shugo
authors.initials: S
authors.lastname: Suzuki
authors.forename: Masanao
authors.initials: M
authors.lastname: Yokohira
authors.forename: Karen L
authors.initials: KL
authors.lastname: Pennington
authors.forename: Bhavana J
authors.initials: BJ
authors.lastname: Dave
authors.forename: Xiufen
authors.initials: X
authors.lastname: Lu
authors.forename: X Chris
authors.initials: XC
authors.lastname: Le
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Cohen
mesh_terms: D000818:Animals; D002101:Cacodylic Acid / Q000031:analogs & derivatives* / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity*; D002467:Cell Nucleus / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D004305:Dose-Response Relationship, Drug; D005260:Female; D002479:Inclusion Bodies / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008780:Methyltransferases / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D013997:Time Factors; D001743:Urinary Bladder / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D019459:Urothelium / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D002273:Carcinogens; C472511:dimethylarsinous acid; D002101:Cacodylic Acid; D008780:Methyltransferases; C532135:AS3MT protein, mouse
keywords: carcinogenesis; genotoxicity; granules; intramitochondrial; intranuclear.; micronuclei